This project proposes to analyze the efficacy, in a mouse model, of a novel chemical compound as an inhibitor of the self-assembly and neurotoxicity of amyloid 2-protein (A2) and potentially the tau protein - the main proteins believed to cause Alzheimer's disease (AD). Despite tremendous research efforts, currently AD has no cure and is developing as a major public health threat with 454,000 new patients diagnosed with AD in the United States each year. A2 is a protein of unknown function that upon aging accumulates in the brain and self- associates into highly toxic oligomers. The oligomers injure susceptible neurons leading to the symptoms seen in AD and go on to form fibrillar polymers that precipitate in the brain as amyloid plaques. In recent years, progress in structural studies of A2 oligomers has revealed key interactions that control formation of these toxic assemblies. We have identified molecular tweezers (MT) as compounds that could compete for these key interactions by specifically binding to the lysine residues involved. We hypothesize that the disruption of these interactions will inhibit A2 assembly and toxicity and thus could lead to a disease-modifying therapy for AD. Our initial data demonstrate that MT can indeed block A2 oligomerization and inhibit toxic effects of A2 in cell culture. With the application of the compound, we see rescue of the A2-induced neuronal dendritic spine depletion and reduction in brain A2 load in a transgenic mouse model of AD. In this project, we will begin to characterize the effects of the protein assembly inhibitors in an advanced mouse model of AD that develops both A2 and tau pathology. Importantly, we will evaluate the cognitive improvements seen with MT treatment in short- and long-term memory and spatial and recognition memory by three behavioral tasks (aim 1A). We plan to identify the changes in brain pathology that occur as a result of treatment by histochemical and biochemical assays by evaluating levels and states of A2, phosphorylated tau, neuro- inflammation, and synaptic density (aim 1B and C). PUBLIC HEALTH RELEVANCE: Relevance to Public Health This project addresses the urgent public health need to develop disease targeting therapy for Alzheimer's disease (AD). The rapidly aging American population and the accelerating costs of AD patient care demand the attention of funding agencies and scientist who have the facilities to aid in any way. We address this urgent need by assessing the utility, in an animal model, of an innovative small molecule inhibitor of amyloid 2-protein assembly, which has a novel mechanism of action and has proven effective in vitro.